Herpesviruses have developed strategies to counteract host defenses so as to allow viruses to infect cells and result in a latent or persistent infection. The goal of this project is to identify and determine the function of herpesvirus proteins that interact with host cell proteins to influence the course of infection. These proteins may allow us to identify new molecules that are important in the human immune system. Programmed cell death (apoptosis) is an antiviral defense mechanism used by the host to eliminate virus-infected cells. Some viruses encode proteins that interfere with signaling pathways for apoptosis. In collaboration with investigators in the LID, we have shown that a protein encoded by an RNA virus induces programmed cell death. This virus, Langat virus, causes encephalitis in mice and is a member of the flavivirus group which includes viruses such as the hepatitis C virus. We have found that infection of cells with Langat virus, or expression of the envelope protein of Langat virus alone, induces cell death. The envelope protein activates a specific protein cleaving enzyme (the caspase-3 protease) that mediates cell death. Induction of programmed cell death by the envelope protein may allow the virus to escape from infected cells so that it can spread to infect other cells. In addition, since the envelope protein of Langat virus has been shown to be important for its neurovirulent properties, the ability of this protein to induce programmed cell death may contribute to the central nervous system disease caused by this virus. The X-linked lymphoproliferative syndrome is a immune deficiency disease that is due to an inability to control infection by Epstein-Barr virus. The disease is due to a mutation in the cellular SAP gene. In collaboration with investigators at the Basel Institute we have shown that the SAP protein interacts with a receptor (2B4) on natural killer cells to activate killing by these cells. In addition, we have shown that patients with the X-linked lymphoproliferative syndrome have a defect in receptor (2B4) mediated lysis of target cells by natural killer cells. The defect in receptor mediated killing may directly contribute to the pathogenesis of X-linked lymphoproliferative disease by reducing the ability of natural killer cells to lyse Epstein-Barr virus-infected cells.